A great number of diseases, for example of auto-immune origin, are treated at present by IgG concentrates and this generated a shortage of IgGs in Europe and in the United-States of America in the last years.
Effectively, there is a growing need for IgG concentrates produced for example from human plasma, which are usually formulated at acidic pH and applicable by intravenous administration. With growing needs for IgGs, the stabilization of intravenously administrable IgG concentrates (IgGIV), intended to be used in therapy, and to be preserved either in liquid form or in lyophilised form, takes on an essential character.
In this respect, it is known that the IgGIVs have to be stabilized, especially in order to avoid the formation of aggregates (oligomers and polymers) capable of activating the complement system, which is associated with the risk of anaphylactic reactions. Furthermore, the presence of dimers in the IgGIVs is correlated with arterial pressure drops in vivo (Bleeker W. K. et al, Blood, 95, 2000. p. 1856-1861). Further physico-chemical deteriorations can also interfere during the storage of IgGs such as, inter alia, oxidation and hydrolysis.
The stabilization of lyophilised or liquid forms of IgGs requires the addition of compounds, selected classically among sugars and aminoacids, in order not only to obtain undenaturated IgG compositions suitable for therapeutical use, but also IgG compositions with an increased storage stability.
The stabilization of lyophilised forms of protein compositions, and especially of IgGs, by addition of specific stabilisers, was investigated in numerous studies. Those cited in scientific papers by M. Pikal, “Freeze-Drying of Proteins, Part 2: Formulation Selection”, Biopharm, 3(9); pp. 26-30 (1990) and by Arakawa et al, Pharm. Res., 1991, 8(3), p. 285-291, demonstrate that the addition of a excipient to protein compositions before lyophilisation, increases the stability during the lyophilisation and/or the stability of the lyophilised product during the storage. Some of these stabilisers, however, are known to be precipitating agents of proteins higher than about 100 kDa. Thus, the use of polyethylene glycol (PEG) 3000-6000 is redhibitory in the freezing phase leading to the lyophilisation of the corresponding protein compositions. Osterberg et al, (Pharm. Res., 1997, 14 (7), p. 892-898) has shown the efficiency of a mixture comprising histidine, sucrose, a non-ionic surface active agent and sodium chloride, for the stabilization of lyophilised forms of recombinant factor VIII, and no improvement of its stability was observed through addition of PEG. Moreover, Guo et al, (Biomacromol., 2002, 3(4), p. 846-849) pointed out, that the lyophilisation of horseradish peroxidase in the presence of PEG does not allow to maintain its native structure. Thus, it appears that the presence of PEG is undesirable.
Lyophilised IgGIV compositions are commercially available for example under the trade marks Polygam™ (American Red Cross), Gammar IV™ (Armour Pharmaceutical Company) and Venoglobulin™ I (Alpha), comprising as stabilisers respectively 2% of glucose, 5% of sucrose and 2% of D-mannitol.
The international patent application WO 97/04801 discloses the effect of stabilization of lyophilised monoclonal antibodies formulations (immunoglobulins of G and E type) comprising specific excipients. From these excipients, the combination of glycine/mannitol was not selected because of lack of efficiency compared with other combinations, such as sucrose/glycine and sucrose/mannitol.
However, it is noted that stabilizers suitable for lyophilised forms of IgGIV could be inefficient for liquid IgGIV compositions.
Thus, commercially available liquid IgGIV compositions comprise specific stabilisers, different from those used in the corresponding lyophilised form. For example, the liquid IgGIV compositions comprising as stabilisers 10% maltose, glycine from 0.16 to 0.24 M and 5% D-sorbitol, are respectively known under the trade marks Gamimune N™, Gamimune N™ 10% (Miles Inc.) and Venoglobulin™ (Alpha).
The different nature of the components used for stabilising. IgG compositions in liquid form and in lyophilised form, incited some authors to investigate identical stabilisers or mixtures of stabilisers allowing to preserve the IgG compositions in both forms. In this respect, recent studies were directed to the stabilization of liquid IgGIV compositions Vigam-S and Vigam Liquid (trademarks of the National Blood Authority, England), and after being lyophilised (Vigam-S), comprising an identical mixture of stabilizers, namely albumin and sucrose (K. Chidwick et al, Vox Sanguinis, 77, 204-209, 1999). The solution Vigam Liquid is however formulated at an acidic pH (pH 5), which is a drawback because of the hydrolysis of sucrose into reducing sugars (fructose and glucose) which condense with amino residues of the lysine of IgG and of albumine, giving an instable Schiff's base evolving into Maillard products (browning of the solution). It is understood that the use of excipients which evolve during the preservation of IgGs is not satisfactory, because it is not possible to control the once onset reaction.
Moreover, some previously cited stabilisers, such as maltose or sucrose, cannot be used without risk in individuals suffering from renal failure and/or from diabetes.
In order to overcome the above cited drawbacks, the Applicant put in practice a unique pharmaceutically acceptable stabilising formulation, fulfilling the purpose of stabilization of both considered preservation forms of IgG and to preserve, even to improve, the therapeutical efficiency of these IgGs.
Such a stabilising formulation has especially the advantage of carrying out only one formulation, which facilitates the control of the starting materials, and brings with reduced manufacturing costs combined with the simplification of production flow sheets.